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Background and ObjectivesTo assess whether increased seizure frequency during pregnancy and postpartum is influenced by epilepsy type, seizure location, and antiseizure medications.MethodsClinical data were collected in a longitudinal prospective database of pregnant women with epilepsy at Brigham and Women's Hospital. Within each individual participant, baseline seizure frequency was calculated for the 9 months before conception, and whether seizure frequency increased during pregnancy or the postpartum period was determined. Seizure frequency was calculated for each 4-week interval during pregnancy. Generalized estimating equations for logistic regression were applied.ResultsNinety-nine patients contributing 114 pregnancies were included from 2013 to 2018. Increased seizure frequency occurred more often during pregnancies of women with focal vs generalized epilepsy (21.1% vs 5.3%, odds ratio [OR] 4.70, 95% confidence interval [CI] 1.00–22.00; p = 0.0497). Among women with focal epilepsy, increased seizure frequency occurred more often in those with frontal lobe epilepsy (OR 8.00, 95% CI 2.19–29.21; p = 0.0017). There was no difference in seizure worsening in the postpartum period between the focal and generalized (11.1% vs 9.1%; p = 0.4478) or frontal and other focal (18.8% vs 6.0%; p = 0.1478) epilepsy groups. Pregnancies on polytherapy had higher odds of seizure worsening compared to monotherapy (OR 8.36, 95% CI 2.07–33.84; p = 0.0029), regardless of the medication or epilepsy type. A lack of preconception seizure freedom was also associated with increased seizure frequency during pregnancy (OR 6.418; p = 0.0076).DiscussionWomen with focal epilepsy have higher likelihood of seizure worsening during pregnancy compared to women with generalized epilepsy; frontal lobe epilepsy poses an especially elevated risk. Polytherapy and lack of preconception seizure freedom are additional predictors for an increased likelihood of seizure worsening.

Objective We examined mode of delivery among pregnant women with epilepsy (PWWE) versus pregnant controls (PC). We hypothesize that PWWE are more likely to deliver by cesarean. Study Design The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an observational, prospective, multicenter investigation of pregnancy outcomes funded by the National Institute of Health (NIH). MONEAD enrolled patients from December 2012 through January 2016. PWWE were matched to PC in a case:control ratio of 3:1. This analysis had 80% power to detect a 36% increase in cesarean frequency assuming a baseline rate of 30% among PC at an α = 0.05. Results This report analyzed 331 PWWE (76%) and 102 PC (24%) who gave birth while enrolled in the study. PWWE and PC had similar rates of cesarean delivery (34.7 vs. 28.6%; p = 0.27). Of women with cesarean, rates of cesarean without labor were similar between groups for those delivering in recruitment hospitals (48.2 vs. 50.0%) but in nonrecruitment hospitals, cesarean rates without labor were over two-fold higher among PWWE than those of PC (68.8 vs. 30.8%; p = 0.023). Receipt of a cesarean after labor did not differ for PWWE compared to PC or by type of antiepileptic drug among the PWWE. Conclusion These findings suggest that the obstetrical experiences of PWWE and PC are similar. An interesting deviation from this observation was the mode of delivery with higher unlabored cesarean rates occurring among PWWE in nonrecruitment hospitals. As the study recruitment hospitals were tertiary academic centers and nonrecruitment hospitals tended to be community-based institutions, differences in perinatal expertise might contribute to this difference. Key Points

Objective To investigate neurophysiologic and neuroimaging characteristics of patients with late onset unexplained epilepsy (LOUE). Methods We performed a retrospective chart review of elderly patients with ICD9 diagnosis codes consistent with epilepsy/seizures. Inclusion criteria included unprovoked seizures, and absence of cortical lesions on magnetic resonance imaging (MRI). Electroencephalograms (EEGs) findings were also analyzed. MRI images were scored for degree of white matter hyperintensities (Fazekas Scale) and mesial temporal atrophy (MTA). Vascular risk factors, and Framingham Heart Study general cardiovascular disease (FHS-CVD) risk scores were compared to controls from the Harvard Aging Brain study (HABS). Results We identified 224 LOUE patients and 8% were drug resistant. Epileptiform abnormalities were captured on EEG in 35%. The location was temporal with left sided predominance in 49%. Fazekas scale consisted of 25% beginning of confluent lesions, and 10% large confluent lesions. MTA scores consisted of 21% moderate-severe hippocampal atrophy. LOUE patients had on average a 2.3% (adjusted), 7.4% (unadjusted) increased FHS-CVD score. Conclusions Our findings highlight LOUE as pharmacosensitive and left temporal predominant. Given the higher prevalence of vascular risk factors, investigations are needed to study their role in pathophysiology. Significance Physicians caring for patients with LOUE should evaluate for vascular risk factors and investigate the presence of hippocampal atrophy.

ObjectivesTo provide information on the effect of the coronavirus disease of 2019 (COVID-19) pandemic on people with epilepsy and provide consensus recommendations on how to provide the best possible care for people with epilepsy while avoiding visits to urgent care facilities and hospitalizations during the novel coronavirus pandemic.MethodsThe authors developed consensus statements in 2 sections. The first was “How should we/clinicians modify our clinical care pathway for people with epilepsy during the COVID-19 pandemic?” The second was “What general advice should we give to people with epilepsy during this crisis? The authors individually scored statements on a scale of −10 (strongly disagree) to +10 (strongly agree). Five of 11 recommendations for physicians and 3/5 recommendations for individuals/families were rated by all the authors as 7 or above (strongly agree) on the first round of rating. Subsequently, a teleconference was held where statements for which there was a lack of strong consensus were revised.ResultsAfter revision, all consensus recommendations received a score of 7 or above. The recommendations focus on administration of as much care as possible at home to keep people with epilepsy out of health care facilities, where they are likely to encounter COVID-19 (including strategies for rescue therapy), as well as minimization of risk of seizure exacerbation through adherence, and through ensuring a regular supply of medication. We also provide helpful links to additional helpful information for people with epilepsy and health providers.ConclusionThese recommendations may help health care professionals provide optimal care to people with epilepsy during the coronavirus pandemic.

IMPORTANCE: Neurodevelopmental disorders are associated with poor health and social outcomes. Population-based data on incidence, age at diagnosis, and demographic variations are essential to identify modifiable risk factors and inform the planning of services and interventions. OBJECTIVES: To assess the incidence and timing of diagnosis of neurodevelopmental disorders during childhood in the US and to evaluate differences by population characteristics. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used nationwide data on birth cohorts nested in the 2000-2014 Medicaid Analytic eXtract and the 2003-2015 IBM MarketScan Research Database on 2 070 541 publicly and 1 309 900 privately insured children enrolled at birth. Data were analyzed between May 1, 2020, and June 30, 2021. MAIN OUTCOMES AND MEASURES: Neurodevelopmental disorders, autism spectrum disorders, attention-deficit/hyperactivity disorder, learning disabilities, speech or language disorders, developmental coordination disorders, intellectual disabilities, and behavioral disorders were identified based on validated algorithms. Kaplan-Meier analyses were used to estimate the incidence and timing of diagnosis, stratified by child’s sex, birth year, maternal age at delivery, and race and ethnicity. RESULTS: The cohorts comprised 2 070 541 publicly insured children (1 045 426 boys [50.5%]) and 1 309 900 privately insured children (667 607 boys [51.0%]) enrolled at birth. By 8 years of age, 23.9% of publicly insured children and 11.0% of privately insured children received a diagnosis of 1 or more neurodevelopmental disorders (autism spectrum disorder, 1.6% and 1.3%; attention-deficit/hyperactivity disorder, 14.5% and 5.8%; learning disability, 1.2% and 0.6%; speech or language disorder, 8.4% and 4.5%; developmental coordination disorder, 0.9% and 0.7%; intellectual disability, 0.7% and 0.1%; and behavioral disorder, 8.4% and 1.5%). Risks were substantially higher among boys (incidence of ≥1 neurodevelopmental disorder by age 8 years for boys vs girls: 30.7% vs 16.7% among publicly insured children and 15.0% vs 6.7% among privately insured children) and White children (30.2% vs 9.1% among Asian children, 23.0% among Black children, 15.4% among Hispanic children, and 22.7% among children of unknown race or ethnicity; information on race and ethnicity was available only for publicly insured children). The association of maternal age and birth year with incidence of neurodevelopmental disorders varied by outcome. Except for attention-deficit/hyperactivity disorder, the diagnosis tended to be established somewhat earlier for privately insured children. The association of race and ethnicity with age at diagnosis varied by outcome. Co-occurring neurodevelopmental disorders were common, especially among children with autism spectrum disorder and intellectual disability (>70% had ≥1 other disorder). CONCLUSIONS AND RELEVANCE: In this population-based cohort study, a relatively high incidence of and co-occurrence of neurodevelopmental disorders as well as the disparity in incidence and timing of diagnosis by insurance type and race and ethnicity were found. These findings represent important public health concerns and underscore the need for timely and accessible developmental assessments and educational services to help reduce the burden of these disorders.

Background and ObjectivesAssess the incidence and factors associated with major depressive episodes (MDEs) and symptoms of depression and anxiety during pregnancy and postpartum periods in pregnant women with epilepsy (PWWE) compared with healthy pregnant women (HPW) and nonpregnant women with epilepsy (NPWWE) in comparable timeframes. Previous studies have reported higher rates of postpartum depression in women with epilepsy compared with women without epilepsy. However, the incidence of MDE using a structured interview during pregnancy and postpartum has not been directly compared with control groups, and the comparison of depression and anxiety symptoms and the role of associated factors remain ambiguous.MethodsThe Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a multicenter NIH-funded prospective observational parallel group cohort study of PWWE and their children. This report examines mood disorders. Unlike previous epilepsy pregnancy studies, the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-IV (SCID) provided lifetime diagnoses, and repeated SCID mood modules assessed for MDE, the a priori primary outcome. Symptoms of depression (Beck Depression Inventory [BDI] and Edinburg Postnatal Depression Scale [EPDS]) and anxiety (Beck Anxiety Inventory [BAI]) were also assessed along with multiple clinical factors.ResultsThis study included PWWE (n = 331) and HPW (n = 102) during pregnancy and postpartum and NPWWE (n = 102) at comparable times. No difference in SCID-diagnosed MDE incidence was found across groups, but BDI depressive symptoms were worse during pregnancy in PWWE vs NPWWE and during postpartum vs HPW and NPWWE. BAI anxiety symptoms were worse during pregnancy in PWWE vs HPW and NPWWE and during postpartum vs HPW. Factors associated with MDE during pregnancy/postpartum for PWWE included >1 seizure/90 days, anticonvulsant polytherapy, unplanned pregnancy, and lifetime history of mood disorder. Suicidal ideation from BDI or EPDS was related to BAI anxiety symptoms.DiscussionAlthough SCID-based MDE did not differ across groups, this prospective study confirms higher rates of psychiatric symptoms in patients with epilepsy during pregnancy and postpartum, provides new data on associated factors, and underscores the importance of anxiety in risk for depression and thoughts of death/dying or suicide. Given the risks, PWWE should be routinely assessed and symptomatic patients should be offered treatment.Trial Registration InformationThis study is registered at ClinicalTrials.gov as NCT01730170.

ImportanceAntidepressant use during pregnancy has been associated with neurodevelopmental disorders in children in some studies. However, results may be explained by uncontrolled confounding by parental mental health status, genetics, and environmental factors.ObjectiveTo evaluate the association between antidepressant use in pregnancy and neurodevelopmental outcomes in children.Design, Setting, and ParticipantsThis cohort study of health care utilization data was separated into cohorts of publicly and privately insured pregnant individuals and their children nested in the Medicaid Analytic eXtract (MAX; 2000-2014) and the IBM MarketScan Research Database (MarketScan; 2003-2015). A total of 1.93 million pregnancies in MAX and 1.25 million pregnancies in MarketScan were recorded. Children were followed from birth until outcome diagnosis, disenrollment, death, or end of study (maximum 14 years). Analyses were conducted between August 2020 and July 2021.ExposuresDispensing of antidepressant medication from gestational week 19 until delivery, the period of synaptogenesis.Main Outcomes and MeasuresNeurodevelopmental disorders in children defined using validated algorithms. Early pregnancy exposure was considered in sensitivity analyses, and approaches to confounding adjustment included propensity score fine stratification, discontinuers comparison, and sibling analyses.ResultsAmong the individuals included in the analysis, there were 145 702 antidepressant-exposed and 3 032 745 unexposed pregnancies; the mean (SD) age among the antidepressant exposed and unexposed was 26.2 (5.7) and 24.3 (5.8) years in MAX and 32.7 (4.6) and 31.9 (4.6) years in MarketScan, respectively; and in MAX, which collected information on race and ethnicity, 72.4% of the antidepressant-exposed and 37.1% of the unexposed individuals were White. Crude results suggested up to a doubling in risk of neurodevelopmental outcomes associated with antidepressant exposure; however, no association was observed in the most fully adjusted analyses. When comparing antidepressant-exposed and unexposed siblings, hazard ratios were 0.97 (95% CI, 0.88-1.06) for any neurodevelopmental disorder, 0.86 (95% CI, 0.60-1.23) for autism spectrum disorder, 0.94 (95% CI, 0.81-1.08) for attention-deficit/hyperactivity disorder, 0.77 (95% CI, 0.42-1.39) for specific learning disorders, 1.01 (95% CI, 0.88-1.16) for developmental speech/language disorder, 0.79 (95% CI, 0.54-1.17) for developmental coordination disorder, 1.00 (95% CI, 0.45-2.22) for intellectual disability, and 0.95 (95% CI, 0.80-1.12) for behavioral disorders. Results were generally consistent for antidepressant classes and drugs and across exposure windows.Conclusions and RelevanceThe results of this cohort study suggest that antidepressant use in pregnancy itself does not increase the risk of neurodevelopmental disorders in children. However, given strong crude associations, antidepressant exposure in pregnancy may be an important marker for the need of early screening and intervention.

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study was a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate). In this report, we examine fetal AED exposure effects on learning and memory functions in 221 six-year-old children (including four sets of twins) whose mothers took one of these AEDs during pregnancy. Their performance was compared with that of a national sample of normally developing six year olds from the standardization sample of the Children's Memory Scale (CMS). The major results of this study indicate that the mean performance levels of children exposed to valproate were significantly below that of the children in the normal comparison group across all seven of the CMS Indexes. With one exception, this finding held up at the subtest level as well. These findings taken together with nonsignificant verbal and nonverbal forgetting scores appear to indicate that, as a group, children exposed to valproate experienced significant difficulty in their ability to process, encode, and learn both auditory/verbal as well as visual/nonverbal material. In addition, they exhibited significant difficulty holding and manipulating information in immediate auditory working memory. However, once the information was learned and stored, the valproate-exposed children appeared to be able to retrieve the information they did learn at normal levels. Finally, the processing, working memory, and learning deficits demonstrated by the valproate-exposed children are dose-related. In contrast to valproate, the findings pertaining to the children exposed to carbamazepine, lamotrigine, and phenytoin in monotherapy are less clear. Therefore, further research will be required to delineate the potential risks to learning and memory functions in children exposed to carbamazepine, lamotrigine, and phenytoin in monotherapy during pregnancy. Additional research employing larger prospective studies will be required to confirm the long-term cognitive and behavioral risks to children of mothers who are prescribed these four AEDs during pregnancy as well as to delineate any potential risks of newer AEDs and to understand the underlying mechanisms of adverse AED effects on the immature brain.

Pregnant women with epilepsy (PWWE) require continuous anti-epileptic drug (AED) treatment to avoid risk to themselves and fetal risks secondary to maternal seizures, resulting in prolonged AED exposure to the developing embryo and fetus. The objectives of this study were to determine whether high-resolution metabolomics is able to link the metabolite profile of PWWE receiving lamotrigine or levetiracetam for seizure control to associated pharmacodynamic (PD) biological responses. Untargeted metabolomic analysis of plasma obtained from 82 PWWE was completed using high-resolution mass spectrometry. Biological alterations due to lamotrigine or levetiracetam monotherapy were determined by a metabolome-wide association study that compared patients taking either drug to those who did not require AED treatment. Metabolic changes associated with AED use were then evaluated by testing for drug-dose associated metabolic variations and pathway enrichment. AED therapy resulted in drug-associated metabolic profiles recognizable within maternal plasma. Both the parent compounds and major metabolites were detected, and each AED was correlated with other metabolic features and pathways. Changes in metabolites and metabolic pathways important to maternal health and linked to fetal neurodevelopment were detected for both drugs, including changes in one‑carbon metabolism, neurotransmitter biosynthesis and steroid metabolism. In addition, decreased levels of 5-methyltetrahydrofolate and tetrahydrofolate were detected in women taking lamotrigine, which is consistent with recent findings showing increased risk of autism spectrum disorder traits in PWWE using AED. These results represent a first step in development of pharmacometabolomic framework with potential to detect adverse AED-related metabolic changes during pregnancy.

OBJECTIVE We sought to ascertain the drivers of the use of anti-seizure medications (ASMs) other than magnesium sulfate (MgSO4) in seizure management in a cohort of pregnant and postpartum women with eclamptic seizure. METHODS Cases of seizure activity attributed to eclampsia from 1995-2015 at 2 large urban academic medical centers were identified and reviewed by a neurologist and an obstetrician. Analyses focused on patterns of ASM utilization among women according to timing, recurrence, posterior reversible encephalopathy syndrome, and specialty consultation with additional sub-analysis focusing on recurrent seizures only. RESULTS 93 cases of eclampsia were identified. 100% of subjects received MgSO4. 52% of women received an ASM in addition to MgSO4. Subjects with seizures occurring post-partum, with >1 seizure, or who had a formal neurology consult were more likely to receive an ASM in addition (risk ratio [RR] 3.05 [95% confidence interval [CI] [1.30-7.11], RR 3.01 [95% CI 1.29-7.02], and RR 6.29 [2.37, 16.71] respectively). Postpartum recurrent seizures or those receiving a neurology consult were also more likely to be treated with ASMs compared to recurrent or comanaged seizures occurring before delivery (RR 1.55 [1.02, 2.37] and 1.65 [1.02, 2.69]). CONCLUSIONS In this retrospective cohort, patients with atypical seizure presentation (e.g., postpartum and/or recurrent) and women who were comanaged with a neurologist were more likely to receive an ASM other than MgSO4.

Changes in Seizure Frequency and Antiepileptic Therapy During Pregnancy Pennell PB, French JA, May RC, et al. N Engl J Med. 2020;383:2547-56. https://pubmed.ncbi.nlm.nih.gov/33369356/. doi:10.1056/NEJMoa2008663.Background:Among women with epilepsy, studies regarding changes in seizure frequency during pregnancy have been limited by the lack of an appropriate nonpregnant comparator group to provide data on the natural course of seizure frequency in both groups.Methods:In this prospective, observational, multicenter cohort study, we compared the frequency of seizures during pregnancy through the peripartum period (the first 6 weeks after birth; epoch 1) with the frequency during the postpartum period (the following 7.5 months after pregnancy; epoch 2). Nonpregnant women with epilepsy were enrolled as controls and had similar follow-up during an 18-month period. The primary outcome was the percentage of women who had a higher frequency of seizures that impaired awareness during epoch 1 than during epoch 2. We also compared changes in the doses of antiepileptic drugs that were administered in the 2 groups during the first 9 months of epoch 1.Results:We enrolled 351 pregnant women and 109 controls with epilepsy. Among the 299 pregnant women and 93 controls who had a history of seizures that impaired awareness and who had available data for the 2 epochs, seizure frequency was higher during epoch 1 than during epoch 2 in 70 (23%) pregnant women and in 23 (25%) controls (odds ratio, 0.93; 95% CI, 0.54-1.60). During pregnancy, the dose of an antiepileptic drug was changed at least once in 74% of pregnant women and in 31% of controls (odds ratio, 6.36; 95% CI, 3.82-10.59).Conclusions:Among women with epilepsy, the percentage who had a higher incidence of seizures during pregnancy than during the postpartum period was similar to that in women who were not pregnant during the corresponding epochs. Changes in doses of antiepileptic drugs occurred more frequently in pregnant women than in nonpregnant women during similar time periods. (Funded by the National Institutes of Health; MONEAD ClinicalTrials.gov number, NCT01730170.)

The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer’s disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD., Imbalance of microglial phenotypes in the aging brain might underlie their involvement in late onset neurodegenerative diseases. Here we report the population structure of microglia in the aged human brain and the reduction of a particular microglia subset in individuals with Alzheimer’s disease .

The ILAE Task Force on Women and Pregnancy conducted a survey among ILAE Chapters of their use of guidelines or recommendations for the management of women with epilepsy during pregnancy. A web-based questionnaire including 10 questions was sent to the 118 ILAE Chapters in December 2017 with repeated reminders until the end of February 2018. In total, 77 chapters (65%) responded, although not to all questions. Out of those responding, 68% reported having guidelines or recommendations, 34% of which were from 2014 or earlier. At least 20% of the guidelines did not include information on possible risk to cognitive development, information regarding specific risks with specific antiepileptic drugs, nor recommendations regarding selection of antiepileptic drugs. Among those responding to the question, 91% reported that recommendations were made regarding folate supplementation, but the recommended dose ranged from 0.4 mg/d to 4 mg/d or more; 34% did not include recommendations regarding drug level monitoring during pregnancy, and 19% did not include guidelines on breastfeeding. Our survey demonstrates that there is a need for the development of up-to-date, globally applicable recommendations for the management of epilepsy during pregnancy. Fil: Tomson, Torbjörn. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia. Karolinska University Hospital. Department of Neurology; Suecia Fil: Battino, Dina. Fondazione IRCCS Istituto Neurologico Carlo Besta. Department of Neurophysiology and Experimental Epileptology. Epilepsy Center; Italia Fil: Bromley, Rebecca. Central Manchester University Hospitals NHS Foundation Trust; Reino Unido. University of Manchester; Reino Unido Fil: Kochen, Sara Silvia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentina Fil: Meador, Kimford J.. University of Stanford; Estados Unidos Fil: Pennell, Page B.. Brigham and Women's Hospital. Harvard Medical School. Department of Neurology. Divisions of Epilepsy and Women's Health; Estados Unidos Fil: Thomas, Sanjeev V.. Sree Chitra Tirunal Institute of Medical Sciences and Technology. Department of Neurology; India

There is limited information on infant drug exposure via breastfeeding by mothers who are receiving antiepileptic drug therapy.To provide direct, objective information on antiepileptic drug exposure through breast milk.This prospective cohort study was conducted between December 2012 to October 2016, with follow-up in children until 6 years of age at 20 sites across the United States. Data were collected via an observational multicenter investigation (Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs [MONEAD]) of outcomes in pregnant mothers with epilepsy and their children. Pregnant women with epilepsy who were aged 14 to 45 years, had pregnancies that had progressed to less than 20 weeks' gestational age, and had measured IQ scores of more than 70 points were enrolled and followed up through pregnancy and 9 postpartum months. Their infants were enrolled at birth. Data were analyzed from May 2014 to August 2019.Antiepileptic drug exposure in infants who were breastfed.The percentage of infant-to-mother concentration of antiepileptic drugs. Antiepileptic drug concentrations were quantified from blood samples collected from infants and mothers at the same visit, 5 to 20 weeks after birth. Concentrations of antiepileptic drugs in infants at less than the lower limit of quantification were assessed as half of the lower limit. Additional measures collected were the total duration of all daily breastfeeding sessions and/or the volume of pumped breast milk ingested from a bottle.A total of 351 women (of 865 screened and 503 eligible individuals) were enrolled, along with their 345 infants (179 female children [51.9%]; median [range] age, 13 [5-20] weeks). Of the 345 infants, 222 (64.3%) were breastfed; the data collection yielded 164 matching infant-mother concentration pairs from 138 infants. Approximately 49% of all antiepileptic drug concentrations in nursing infants were less than the lower limit of quantification. The median percentage of infant-to-mother concentration for all 7 antiepileptic drugs and 1 metabolite (carbamazepine, carbamazepine-10,11-epoxide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, valproate, and zonisamide) ranged from 0.3% (range, 0.2%-0.9%) to 44.2% (range, 35.2%-125.3%). In multiple linear regression models, maternal concentration was a significant factor associated with lamotrigine concentration in infants (Pearson correlation coefficient, 0.58; P .001) but not levetiracetam concentration in infants.Overall, antiepileptic drug concentrations in blood samples of infants who were breastfed were substantially lower than maternal blood concentrations. Given the well-known benefits of breastfeeding and the prior studies demonstrating no ill effects when the mother was receiving antiepileptic drugs, these findings support the breastfeeding of infants by mothers with epilepsy who are taking antiepileptic drug therapy.

ObjectiveTo examine occurrence of severe adverse fetal outcomes (SAO), including fetal loss and major congenital malformations (MCMs), in pregnant women with epilepsy (PWWE) vs healthy pregnant women (HPW).MethodsThe Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes for both mother and child, which enrolled women December 2012 through January 2016.ResultsThe 351 PWWE had 365 conceptions, and 105 HPW had 109 conceptions. SAOs occurred more often in PWWE (7.9%) vs HPW (1.9%) (p = 0.025) with odds ratio (OR) 4.45 (95% confidence intervals [CI] 1.04–19.01). There were no significant differences for fetal loss (2.8% vs 0%, p = 0.126) or MCMs (5.2% vs 1.9%, p = 0.185; OR 2.86, 95% CI 0.65–12.53) individually. No fetal losses in PWWE appeared to be related to acute seizures. Outcomes were not affected by periconceptional folate, unplanned/unwanted pregnancies, prior maternal pregnancy history, or antiepileptic drug (AED) blood levels, except for an AED level effect for fetal loss that appeared to be due to polytherapy. Combined maternal or paternal family history of MCM was marginally associated with increased SAOs (p = 0.046).ConclusionsThe findings provide additional information on risks of SAOs in PWWE, assessing effects of both AED levels and periconceptional folate. Group differences in average enrollment gestational age could have affected fetal loss results. Analyses are limited by small sample sizes as the MONEAD study was not powered for these secondary outcomes. The large majority of pregnancies in women with epilepsy do not have SOAs.

Patients with neuropsychiatric disease may benefit from repetitive transcranial magnetic stimulation as a nonpharmacologic alternative to relieve symptoms of major depression, obsessive compulsive disorder, and perhaps other syndromes such as epilepsy. We present a case of repetitive transcranial magnetic stimulation treatment as an adjunct therapy for a patient experiencing refractory epileptic seizures during the third trimester of pregnancy. Notably, the patient tolerated repetitive transcranial magnetic stimulation well, without adverse events, and delivered a healthy child. We also summarize the current literature pertaining to therapeutic repetitive transcranial magnetic stimulation use during pregnancy.

OBJECTIVE To determine how early lamotrigine clearance (LTG-CL/F) increases during early pregnancy in women with epilepsy and to quantify the relationship of LTG-CL/F to estradiol concentrations and gestational week. METHODS This was a multicenter, observational study of pregnant women with epilepsy on lamotrigine and no interacting concomitant medications, employing frequent blood sampling prior to and early in pregnancy. A population mixed-effects modeling approach was used to describe the relationship between LTG-CL/F and gestational week and between LTG-CL/F and estradiol. Akaike information criterion (AIC) compared goodness of fit between final models and a generalized estimating equation to compare differences between low and high percentage LTG-CL/F change groups (p

OBJECTIVE: We analyzed current prescribing patterns for antiepileptic drugs (AEDs) in pregnant women with epilepsy (PWWE) at 20 USA tertiary epilepsy centers. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multi-center investigation of pregnancy outcomes for both mother and child, which enrolled women from December 2012 to January 2016. Inclusion criteria for PWWE included ages 14–45 years and up to 20 weeks gestational age. Exclusion criteria included history of psychogenic non-epilepstic spells, expected IQ

ObjectiveTo assess the relative risk of oral clefts associated with maternal use of high and low doses of topiramate during the first trimester for epilepsy and nonepilepsy indications.MethodsThis population-based study nested in the US 2000–2010 Medicaid Analytic eXtract included a cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery. Oral clefts were defined as the presence of a recorded diagnosis in claims during the first 90 days after birth. Women with a topiramate dispensing during the first trimester were compared with those without any dispensing and with an active reference group of women with a lamotrigine dispensing during the first trimester. Risk ratios (RRs) were estimated with generalized linear models with fine stratification on the propensity score of treatment to control for potential confounders. Stratified analyses by indication of use and dose were conducted.ResultsThe risk of oral clefts at birth was 4.1 per 1,000 in the 2,425 infants born to women exposed to topiramate compared with 1.1 per 1,000 in the unexposed group (RR 2.90, 95% confidence interval [CI] 1.56–5.40). The RR among women with epilepsy was 8.30 (95% CI 2.65–26.07); among women with other indications such as bipolar disorder, it was 1.45 (95% CI 0.54–3.86). The median daily dose for the first prescription filled during the first trimester was 200 mg for women with epilepsy and 100 mg for women without epilepsy. For topiramate monotherapy, the RR for oral clefts associated with doses ≤100 mg was 1.64 (95% CI 0.53–5.07) and for doses >100 mg it was 5.16 (95% CI 1.94–13.73). Results were similar when lamotrigine was used as a reference group.ConclusionThe increased risk of oral clefts associated with use of topiramate early in pregnancy was more pronounced in women with epilepsy, who used higher doses.

Neuroactive steroids have rapid, nongenomic effects on neuronal excitability. The effects in humans are less clear. We compared seizure control and concentrations of neuroactive steroids, known to influence neuroexcitability in animal studies, in pregnant women. Participants were prospectively followed throughout pregnancy with seizure-medication diaries and blood samples, assayed for steroid concentrations with gas chromatography-mass spectrometry. Baseline seizure frequency was calculated for the preconception year, and it was determined if seizure frequency was increased in each trimester. The Wilcoxon rank-sum test was used to compare neuroactive steroid concentrations in between the group with increased frequency to the group without, as calculated for the respective trimester, with the Holm-Bonferroni method to correct for multiple comparisons. Among eighty-three pregnancies included, twenty-eight had increased seizure frequency during at least one trimester (15, 18 and 10, respectively) compared to preconception seizure frequency. Allopregnanolone concentrations were lower in the 3(rd) trimester (p< 0.001), with a similar trend in the 1(st) (p=0.08), for pregnancies with increased compared to those with stable seizure frequency. Other neuroactive steroid concentrations were similar. Our findings suggest that lower allopregnanolone concentrations are associated with increased seizure frequency during pregnancy. Validation of these finding in a larger cohort has potential important clinical applications.

Importance The neurodevelopmental risks of fetal exposure are uncertain for many antiseizure medications (ASMs). Objective To compare children at 2 years of age who were born to women with epilepsy (WWE) vs healthy women and assess the association of maximum ASM exposure in the third trimester and subsequent cognitive abilities among children of WWE. Design, setting, and participants The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicenter investigation of pregnancy outcomes that enrolled women from December 19, 2012, to January 13, 2016, at 20 US epilepsy centers. Children are followed up from birth to 6 years of age, with assessment at 2 years of age for this study. Of 1123 pregnant women assessed, 456 were enrolled; 426 did not meet criteria, and 241 chose not to participate. Data were analyzed from February 20 to December 4, 2020. Main outcomes and measures Language domain score according to the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), which incorporates 5 domain scores (language, motor, cognitive, social-emotional, and general adaptive), and association between BSID-III language domain and ASM blood levels in the third trimester in children of WWE. Analyses were adjusted for multiple potential confounding factors, and measures of ASM exposure were assessed. Results The BSID-III assessments were analyzed in 292 children of WWE (median age, 2.1 [range, 1.9-2.5] years; 155 female [53.1%] and 137 male [46.9%]) and 90 children of healthy women (median age, 2.1 [range, 2.0-2.4] years; 43 female [47.8%] and 47 male [52.2%]). No differences were found between groups on the primary outcome of language domain (-0.5; 95% CI, -4.1 to 3.2). None of the other 4 BSID-III domains differed between children of WWE vs healthy women. Most WWE were taking lamotrigine and/or levetiracetam. Exposure to ASMs in children of WWE showed no association with the language domain. However, secondary analyses revealed that higher maximum observed ASM levels in the third trimester were associated with lower BSID-III scores for the motor domain (-5.6; 95% CI, -10.7 to -0.5), and higher maximum ASM doses in the third trimester were associated with lower scores in the general adaptive domain (-1.4; 95% CI, -2.8 to -0.05). Conclusions and relevance Outcomes of children at 2 years of age did not differ between children of WWE taking ASMs and children of healthy women. Trial registration ClinicalTrials.gov Identifier: NCT01730170.

We examined the utility of screening instruments to identify risk factors for suicidal ideation (SI) in a population of women with neuropsychiatric illnesses at high risk for postpartum depression. Pregnant women with neuropsychiatric illness enrolled prior to 20 weeks of gestation. Follow-up visits at 4-8-week intervals through 13 weeks postpartum included assessment of depressive symptoms with both clinician and self-rated scales. A total of 842 women were included in the study. Up to 22.3% of postpartum women admitted SI on rating scales, despite the majority (79%) receiving active pharmacological treatment for psychiatric illness. Postpartum women admitting self-harm/SI were more likely to meet criteria for current major depressive episode (MDE), less than college education, an unplanned pregnancy, a history of past suicide attempt, and a higher score on the Childhood Trauma Questionnaire. In women with a history of neuropsychiatric illness, over 20% admitted SI during the postpartum period despite ongoing psychiatric treatment. Patient-rated depression scales are more sensitive screening tools than a clinician-rated depression scale for +SI in the postpartum period.

We could not agree more with the comment on our editorial1 submitted by Dr. Sethi. Drs. Tomson, Meador, and I are members of the International League Against Epilepsy (ILAE) Task Force on Women and Pregnancy. Our first goal has been education of healthcare providers across a variety of specialties and disciplines, especially because epilepsy care is often delivered by generalist MDs and non-MD providers in low- and middle-income countries in Asia and Africa. We have placed emphasis on the known different levels of risk between the antiseizure medicines and the importance of pregnancy planning, with optimization of the medicine and vitamin regimen before conception. Dr. Sethi's suggestion of also bringing it to the attention of healthcare policy makers and planners is an equally important endeavor. One approach could be to highlight that by restricting AED access to save money, the ultimate national costs in the loss of productivity in patients with epilepsy, and in supporting the healthcare and educational needs of children of women with epilepsy, are probably far greater. The ILAE is aware of this problem and is working to understand and solve this difficult dilemma.

Merely 20 years ago, a report of the Quality Standards Subcommittee of the American Academy of Neurology recommended that antiepileptic drug (AED) selection for pregnant women with epilepsy should be based on the AED “deemed most appropriate for her seizure type.”1 Scientifically, lumping all AEDs together when chemical structures and mechanisms of action differ greatly was questionable, but the evidence for differential effects on fetal outcomes was sparse. Multiple research studies have now made it clear that the level of risk for major congenital malformation (MCMs) differs substantially among AEDs. The prevalence of MCMs is highest with valproate monotherapy2,3 compared to other monotherapies, and includes neural tube defects, heart malformations, cleft palate, hypospadias, and polydactyly. Likewise, the prevalence of MCMs is higher in polytherapy combinations that include valproate, compared to polytherapies that exclude valproate. MCM rates with some AED monotherapies even approximate the rates in the general population (e.g., levetiracetam, lamotrigine).2,3

With the aging of the US population, the incidence of epilepsy will increase, with 25 to 50% of new cases with no identifiable etiology diagnosed as late-onset unexplained epilepsy (LOUE). In the current targeted review, we discuss the possible role of cerebral small vessel ischemic disease, accumulation of amyloidβ and hyperphosphorylated tau, and sleep apnea as potential pathophysiologic mechanisms explaining LOUE. We highlight the impact of these processes on cognition and avenues for diagnosis and treatment.

ObjectiveEmerging evidence suggests potential positive neuropsychological effects of periconceptional folate in both healthy children and children exposed in utero to antiseizure medications (ASMs). In this report, we test the hypothesis that periconceptional folate improves neurodevelopment in children of women with epilepsy by re-examining data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study.MethodsThe NEAD study was an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes in 311 children of 305 women with epilepsy treated with ASM monotherapy. Missing data points were imputed with Markov chain Monte Carlo methods. Multivariate analyses adjusted for multiple factors (e.g., maternal IQ, ASM type, standardized ASM dose, and gestational birth age) were performed to assess the effects of periconceptional folate on cognitive outcomes (i.e., Full Scale Intelligence Quotient [FSIQ], Verbal and Nonverbal indexes, and Expressive and Receptive Language indexes at 3 and 6 years of age, and executive function and memory function at 6 years of age).ResultsPericonceptional folate was associated with higher FSIQ at both 3 and 6 years of age. Significant effects for other measures included Nonverbal Index, Expressive Language Index, and Developmental Neuropsychological Assessment Executive Function at 6 years of age, and Verbal Index and Receptive Language Index at 3 years of age. Nonsignificant effects included Verbal Index, Receptive Index, Behavior Rating Inventory of Executive Function–Parent Questionnaire Executive Function, and General Memory Index at 6 years of age, and Nonverbal Index and Expressive Index at 3 years of age.ConclusionsUse of periconceptional folate in pregnant women with epilepsy taking ASMs is associated with better cognitive development.ClinicalTrials.gov identifier:NCT00021866.

ABSTRACT Child-bearing years are often the most precarious management period in the life of a woman with epilepsy. This article reviews the results of many different studies with findings that enable the healthcare team to make confident decisions and recommendations during these critical periods. Preconceptional planning, effective contraception and folic acid supplementation are important fundamentals in preparation for pregnancy. There is growing evidence to avoid valproic acid use during the child-bearing years. Emerging data on congenital malformations and neurocognitive outcomes are available for some of the second-generation antiepileptic drugs and appear reassuring for lamotrigine and levetiracetam. Also reviewed are the benefits of postpartum drug tapers and favorable breastfeeding facts. Counseling the mother and her family on medication choices enables the healthcare team to implement informed decisions that are beneficial for the mother and child.

OBJECTIVE. Folic acid supplementation during the periconceptual period has been shown to improve cognitive outcomes in children of women with epilepsy taking antiseizure medications (ASMs). The dose of folic acid necessary to provide positive cognitive outcomes is unclear. In many countries including the United States, food is fortified with folic acid, but no data exists on how food fortification may affect cognition in children with fetal-ASM exposure. This study evaluates the effect of dietary folate from natural folates plus folic acid fortification, separate from folic acid vitamin supplements, on age-6 year IQ in children with fetal-ASM exposure. METHODS. Data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study was retrospectively analyzed for this investigation. Assessment of nutrient intake was conducted using the Block Food Frequency Questionnaire-98. The primary outcome of the present study was to assess association of maternal pre-pregnancy nutrient levels to child age-6 IQ. RESULTS. Folate from food alone without supplement was not associated with improvement of age-6 IQ in children with fetal ASM exposure (95% CI: −11.7 – 2.3, p = 0.187). Periconceptual folate supplement use was associated with a 10.1 point higher age-6 IQ (95% CI: 5.2 – 15.0, p

Although prenatal exposure to antiepileptic drugs (AEDs) is known to impart relatively higher risks of major congenital malformations, prospective studies have provided refined data that allow us to differentiate the risks of different types and doses of AEDs. As the number of AED prescriptions has dramatically increased in reproductive-aged women with a variety of neuropsychiatric indications, the evolving concepts learned from studies in women with epilepsy can be applied to a much larger group of pregnant women to improve child outcomes while maintaining maternal disease control. In addition to careful selection of the type of medication, the amount of fetal exposure at conception and in the first trimester probably matters across all AEDs. Some AED polytherapy regimens are not associated with a higher risk of malformations, although other outcomes have not yet been formally studied. The individual woman’s drug target concentration should be established preconception and maintained during pregnancy, to prevent seizure worsening. Substantial pharmacokinetic changes occur with many of the medications during pregnancy and postpartum, and interindividual variability supports the use of therapeutic drug monitoring for most AEDs. During pregnancy, vigilance and close monitoring should also include intrauterine fetal growth, obstetric complications, and neonatal complications. Breastfeeding can provide additional neurodevelopmental benefit and should be an option for women on AEDs. Knowledge of these key principles enhances our ability to make treatment recommendations with resultant improved maternal and child outcomes. Additional prospective studies are needed to further define the risk–benefit ratio across a variety of medications, dosing strategies, and neuropsychiatric disorders.

Epilepsy and antiepileptic drugs affect the menstrual cycle, aspects of contraception, reproductive health, pregnancy, and menopause through alteration of sex steroid hormone pathways. Sex steroid hormones often have an effect on seizure frequency and may alter the level of some antiepileptic drugs. Approximately one-third of women experience an increase in perimenstrual and/or periovulatory seizure frequency. Some women experience an increase in seizure frequency during pregnancy. Balancing maternal seizure control and the risk of congenital malformations associated with fetal antiepileptic drug exposure may be challenging. Some antiepileptic drugs are associated with cognitive and behavioral teratogenesis and should be avoided if possible during pregnancy.

The clinical management of women with epilepsy on antiepileptic drugs (AEDs) during pregnancy presents unique challenges. The goal of treatment is optimal seizure control with minimal in utero fetal exposure to AEDs in an effort to reduce the risk of structural and neurodevelopmental teratogenic effects. This paper reviews the following key issues pertaining to women with epilepsy during pregnancy: AED pharmacokinetics; clinical management of AEDs; seizure frequency; major congenital malformation; neurodevelopmental outcomes; perinatal complications; and breast feeding.

This study used the most recent national data on epilepsy from the 2017 National Health Interview Survey (NHIS) to examine the distribution of types of provider visits in the last 12 months among 2.9 million adult respondents aged ≥ 18 years with active epilepsy (self-reported doctor-diagnosed epilepsy taking antiseizure medications and/or having ≥ 1 seizure in the past year) and compared these estimates with 2010 NHIS data. We calculated age-standardized percentages of visits to a general doctor and an epilepsy specialist during the past 12 months, accounting for the complex survey design. Among US adults with active epilepsy in 2017, 27.1% saw a general doctor only, 9.0% saw a neurologist/epilepsy specialist only, 53.0% visited both a general doctor and a neurologist/epilepsy specialist, and 11.4% did not see either a general doctor or a neurologist/specialist. Overall, 62.0% [95% confidence interval (CI) = 55.2%–67.5%] of adults with active epilepsy visited a neurologist or epilepsy specialist in the past year. A visit in the past 12 months with both provider types was not significantly different in 2017 compared with 2010 (53.0% vs 46.2%) while seeing a general doctor only had declined (41.8% vs 27.1%, p, Highlights • We used NHIS data to examine past 12-month provider visits for adults with epilepsy. • In 2017, 62% of adults visited a neurologist or epilepsy specialist in the past year. • In 2017, 27% of US adults with epilepsy saw a general doctor only. • In 2017, 11% of adults did not see either a general doctor or a neurologist/specialist. • Past 12-month visits with both provider types were the same in 2017 as in 2010.

IMPORTANCE: There is limited information on infant drug exposure via breastfeeding by mothers who are receiving antiepileptic drug therapy. OBJECTIVE: To provide direct, objective information on antiepileptic drug exposure through breast milk. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted between December 2012 to October 2016, with follow-up in children until 6 years of age at 20 sites across the United States. Data were collected via an observational multicenter investigation (Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs [MONEAD]) of outcomes in pregnant mothers with epilepsy and their children. Pregnant women with epilepsy who were aged 14 to 45 years, had pregnancies that had progressed to less than 20 weeks’ gestational age, and had measured IQ scores of more than 70 points were enrolled and followed up through pregnancy and 9 postpartum months. Their infants were enrolled at birth. Data were analyzed from May 2014 to August 2019. EXPOSURES: Antiepileptic drug exposure in infants who were breastfed. MAIN OUTCOMES AND MEASURES: The percentage of infant-to-mother concentration of antiepileptic drugs. Antiepileptic drug concentrations were quantified from blood samples collected from infants and mothers at the same visit, 5 to 20 weeks after birth. Concentrations of antiepileptic drugs in infants at less than the lower limit of quantification were assessed as half of the lower limit. Additional measures collected were the total duration of all daily breastfeeding sessions and/or the volume of pumped breast milk ingested from a bottle. RESULTS: A total of 351 women (of 865 screened and 503 eligible individuals) were enrolled, along with their 345 infants (179 female children [51.9%]; median [range] age, 13 [5-20] weeks). Of the 345 infants, 222 (64.3%) were breastfed; the data collection yielded 164 matching infant-mother concentration pairs from 138 infants. Approximately 49% of all antiepileptic drug concentrations in nursing infants were less than the lower limit of quantification. The median percentage of infant-to-mother concentration for all 7 antiepileptic drugs and 1 metabolite (carbamazepine, carbamazepine-10,11-epoxide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, valproate, and zonisamide) ranged from 0.3% (range, 0.2%-0.9%) to 44.2% (range, 35.2%-125.3%). In multiple linear regression models, maternal concentration was a significant factor associated with lamotrigine concentration in infants (Pearson correlation coefficient, 0.58; P

Importance Biological sex and sociocultural gender represent major sources of diversity among patients, and recent research has shown the association of sex and gender with health. A growing body of literature describes widespread associations of sex and gender with cells, organs, and the manner in which individual patients interact with health care systems. Sex- and gender-informed medicine is a young paradigm of clinical practice and medical research founded on this literature that considers the association of sex and gender with each element of the disease process from risk, to presentation, to response to therapy. Observations Characteristics that underlie sex and gender involve both endogenous and exogenous factors that change throughout the life course. This review details clinical examples with broad applicability that highlight sex and gender differences in the key domains of genetics, epigenomic modifiers, hormonal milieu, immune function, neurocognitive aging process, vascular health, response to therapeutics, and interaction with health care systems. These domains interact with one another in multidimensional associations, contributing to the diversity of the sex and gender spectra. Novel research has identified differences of clinical relevance with the potential to improve care for all patients. Conclusions and Relevance Clinicians should consider incorporating sex and gender in their decision-making to practice precision medicine that integrates fundamental components of patient individuality. Recognizing the biological and environmental factors that affect the disease course is imperative to optimizing care for each patient. Research highlights the myriad ways sex and gender play a role in health and disease. However, these clinically relevant insights have yet to be systematically incorporated into care. The framework described in this review serves as a guide to help clinicians consider sex and gender as they practice precision medicine.

Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimer’s disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.

To determine how early lamotrigine clearance (LTG-CL/F) increases during early pregnancy in women with epilepsy and to quantify the relationship of LTG-CL/F to estradiol concentrations and gestational week.This was a multicenter, observational study of pregnant women with epilepsy on lamotrigine and no interacting concomitant medications, employing frequent blood sampling prior to and early in pregnancy. A population mixed-effects modeling approach was used to describe the relationship between LTG-CL/F and gestational week and between LTG-CL/F and estradiol. Akaike information criterion (AIC) compared goodness of fit between final models and a generalized estimating equation to compare differences between low and high percentage LTG-CL/F change groups (p 0.05).Twenty-five pregnancies (22 participants) were available. Increases in LTG-CL/F were present at 5 weeks gestational age. Both estradiol and gestational week were highly correlated with LTG-CL/F changes; LTG-CL/F increased at the rate of 0.115l/h for every gestational week and 0.844l/h for every 1ng/ml of estradiol, with women in the high LTG-CL/F percentage change group changing at a faster rate (p 0.001). Models using gestational week performed better than models using estradiol.Gestational week was a better predictor of changes in LTG-CL/F than estradiol concentration and may reflect additional factors, although neither was robust enough to use clinically due to substantial interpatient variability. Changes in LTG-CL/F begin as early as the 5th gestational week, often before women know they are pregnant, emphasizing the importance of planning and early detection of pregnancy and consideration of early implementation of therapeutic drug monitoring. Ann Neurol 2018;84:556-563.

Objective The objectives of this study were to investigate the effect of age on pharmacokinetic parameters of lamotrigine (LTG) and estimate parameter variability. Methods Patients (>18 years old) who were already on a steady-state dose of LTG therapy with no interacting comedications were enrolled. Patients with significant cardiac disease, severe kidney dysfunction, or moderate-to-severe liver dysfunction were excluded. Fifty milligrams of a stable-labeled intravenous LTG formulation (SL-LTG) replaced 50 mg of a patient's normal daily oral LTG dose. Thirteen blood samples were collected in each person over 96 hours. SL-LTG and unlabeled LTG concentrations were measured simultaneously by gas chromatography-mass spectrometry. Concentration-time data were analyzed by nonlinear mixed-effects modeling (NONMEM version 7.3). Results Twenty-eight patients representing 16 young (18-48 years old) and 12 elderly (63-87 years old) patients were included, yielding 382 unlabeled and 351 SL-LTG concentrations. A two-compartment model with first-order absorption and elimination adequately described the plasma concentration-time data. Bioavailability of oral LTG was approximately 74% and did not differ by age. LTG clearance was 27.2% lower in elderly than in young patients (1.80 L/h for a 70-kg patient). Significance Although LTG bioavailability was not affected by age, LTG clearance was 27.2% lower in elderly versus young patients of comparable body weight, possibly indicating lower dosages being needed in this population.

ObjectiveTo compare the proportions of unintended pregnancies, prenatal vitamin or folic acid (PNVF) use, adequate prenatal care visits, and breastfeeding among women with epilepsy (WWE) to women without epilepsy (WWoE).MethodsThe Pregnancy Risk Assessment Monitoring System (PRAMS) is an annual survey of randomly sampled postpartum women administered by the Centers for Disease Control and Prevention. We used PRAMS data from 13 states from 2009 to 2014 to compare the primary outcomes in WWE and WWoE, as well as our secondary outcomes of contraception practices, newborn outcomes, and time to recognition of pregnancy. We adjusted for maternal age, race, ethnicity, and socioeconomic status (SES), and we calculated odds ratios for these outcomes using logistic regression.ResultsThis analysis included 73,619 women, of whom 541 (0.7%) reported epilepsy, representing 3,442,128 WWoE and 26,635 WWE through weighted sampling. In WWE, 55% of pregnancies were unintended compared to 48% in WWoE. After adjustment for covariates, epilepsy was not associated with unintended pregnancy or with inadequate prenatal care. WWE were less likely to report breastfeeding but more likely to report daily PNVF use. Newborns of WWE had higher rates of prematurity.ConclusionsAlthough planning for pregnancy is of utmost importance for WWE, more than half the pregnancies in WWE were unintended. Maternal age and SES differences likely contribute to the higher rates in WWE compared to WWoE. The proportion of women reporting breastfeeding is lower in WWE despite studies indicating the safety of breastfeeding in WWE.

Personalized treatment for women with epilepsy is essential, and requires thorough weighing of the risks and benefits of the initial diagnostic and therapeutic options chosen, with readjustments of the antiepileptic regimen throughout the patient's life.Approximately one-third of women with epilepsy have a catamenial pattern, and the most common pattern is an increase in seizure frequency in the perimenstrual phase. These women are also more likely to experience a decrease in seizure frequency during pregnancy and menopause. A good treatment option for catamenial epilepsy is still lacking.For contraception, an intrauterine device is currently the preferred choice. Prior to conception, it is advisable to review the known impact of different antiepileptic drugs on the developing fetus and to optimize the patient's treatment regimen. Pregnancy registries and observational studies have provided key data and continue to refine our understanding of the risks to the structural and cognitive development of the fetus of specific antiepileptic drugs, including polytherapies and newer medications. Different studies consistently report that valproic acid has notably high relative risks for congenital malformations, lower IQ, and features of autism. During pregnancy, there is growing evidence that therapeutic dose monitoring is beneficial for seizure control. Counseling about seizure safety and minimizing provoking factors during the peripartum period is important for the patient with epilepsy.Clinical studies continue to investigate the complex relationship between cycling sex steroid hormones, epilepsy, and antiepileptic medications, with hopes to better explain drug clearance changes during pregnancy, changes in seizure frequency, and neuroendocrine abnormalities. Thorough understanding of these key factors and a continuous review of literature for updated data on different treatment options will enable optimal treatment recommendations that will improve the health of women with epilepsy and their children.

Over a million women with epilepsy are of childbearing age in the USA and require careful consideration of not only type of antiepileptic drug (AED) but also dosage, in the event of a planned or unplanned pregnancy. Careful selection of AEDs can lower the potential adverse effects of AEDs while maintaining seizure control for the health of not only on the patient, the mother, but also the unborn fetus. The number of treatment options has increased significantly in the last 20 years and remarkable progress has been made in characterizing the risks AEDs pose to pregnant women and fetuses. There are now robust data on teratogenesis, a growing body of data on neonatal/obstetrical outcomes and on neurodevelopmental problems associated with each AED, and some data about seizure control during pregnancy. Based on clinical evidence so far, levetiracetam and lamotrigine have emerged as the safest during pregnancy, although others may also be suitable. Despite being a common belief, not all polytherapy combinations may be detrimental, especially when avoiding valproate and topiramate. Here, we review the available clinical research, highlighting recent findings and provide thoughts for future directions in the field.

Objective:To assess whether first-trimester exposure to pregabalin is associated with an increased risk of major congenital malformations, as recently suggested in a pregnancy registry study.Methods:We performed a cohort study nested in the US Medicaid Analytic eXtract (MAX). The study population included 1,323,432 pregnancies resulting in a live-born infant between 2000 and 2010. We examined the risk of major congenital malformations among infants born to women exposed to pregabalin during the first trimester compared with women unexposed to anticonvulsants. We used propensity score fine stratification to control for >50 potential confounders, and we estimated relative risks (RRs) and 95% confidence intervals (CIs) in generalized linear models. The analyses were replicated in the Truven Health MarketScan Commercial Database (MarketScan). Pooled estimates based on the adjusted RR produced in MAX, MarketScan, and the previous registry study were calculated.Results:Of 477 infants exposed to pregabalin during the first trimester in MAX, 28 (5.9%) had malformations compared to 3.3% in nonexposed infants. The crude RR of major congenital malformations for pregabalin was 1.80 (95% CI 1.26–2.58). After propensity score adjustment, the RR moved to 1.16 (95% CI 0.81–1.67). Restriction to pregabalin monotherapy and sensitivity analyses produced similar results. The adjusted RR for major congenital malformations for the 174 infants exposed in MarketScan was 1.03 (95% CI 0.56–1.90). The pooled RR was 1.33 (95% CI 0.83–2.15) for pregabalin any use and 1.02 (95% CI 0.69–1.51) for pregabalin monotherapy.Conclusions:Findings did not confirm the suggested teratogenic effects of pregabalin, although they cannot rule out the possibility of a small effect.